The advantages of using hyaluronic acid and its salts (HA) as an eye or joint fluid replacement are well known. See for example, U.S. Pat. No. 4,141,973 to Balazs, and U.S. Pat. No. 4,517,795 to Bracke et al and U.S. Pat. No. 2,975,104 to Warren. See also copending patent application Ser. No. 555,224 and Ser. No. 555,310 both filed Nov. 25, 1983. Most uses for hyaluronic acid or its salts require high molecular weight polymer. HA products such as Hylartil (Pharmacia as per Balazs) have a high molecular weight but they are also highly viscous. Such a viscous product might be ideal for some uses (i.e. reduction of adhesion formation post surgery); however, HA for injection should preferably be of low viscosity and filterable especially filter sterilizable. Some new extraction processes produce low viscosity HA but it is also of low molecular weight (Sterivet product, Bracke, U.S. Pat. No. 4,517,195, and Shimada and Matsumura, 1975). Obviously, this has some advantage for injectability but its low molecular weight requires use of larger doses (5.0 ml of Sterivet vs. 2.0 ml of Pharmacia product). Also, the Sterivet HA is not filter sterilizable and must be heat sterilized.
To our knowledge, no one has described procedures to obtain high molecular weight HA from low molecular weight HA. However, a method of lowering viscosity by adjusting pH has been described in the literature (Mitra et al, 1983; Mitra, Raghunathan et al, 1983 and Sheehan et al, 1983). These groups do not discuss molecular weight but relate this reversible pH phenomenon to a conformational change in the HA molecule. They have theorized that the lowered viscosity is probably due to an increased flexibility of the polymer which may be the result of an order-to-disorder transition. This suggests instability of polymer and eventually lowered molecular weight. Swann (1969) proposed that the loss of viscosity may be due to the ionization of hydroxyl groups and the disruption of interresidue hydrogen bonding within the random coil of the .alpha.-helix structure of Ha. Interestingly, this viscosity-reducing phenomenon resulting from high pH can be totally reversed by dropping the pH below 3.0. In fact, at pH approximately 2.5 a viscoelastic putty is produced (Gibbs et al, 1968). It is also of interest that the high pH low viscosity HA is quite difficult to filter sterilize. A gel layer builds up in front of the filter making large volume filtration essentially impossible.